In order to understand the mechanisms by which T lymphocytes recognize foreign antigens, one must account for the finding that such reactions also involve self-antigens encoded in the major histocompatibility complex (MHC or H-2 in the mouse). Likewise, an explanation for the phenomenon of alloreactivity, that is, the response to foreign MHC antigens of the species is needed. The object of this proposal is to determine the mechanisms by which T cells recognize both foreign and self H-2 antigens in mouse T cell responses. We propose to carry out experiments that examine this process using whole T cell populations, T cell populations highly enriched for reactivity to particular foreign MHC antigens, individual T cells either per se or as products of cloned T cell lines, and at the level of isolated antigen-binding receptors derived from such cells. Probes for specific T cell receptors will be both antigen and anti-idiotypic antibody. We have also prepared a large amount of an antibody that reacts with receptor material from mouse T cells, which we will use for isolation of T cell receptors from cloned T cell lines. We will test such receptor preparations for their ability to bind antigen, both self and non-self MHC antigens and the foreign, non-MHC antigen to which the T cell lines respond. We will characterize such receptors in terms of their size and serological characteristics, in particular the possession of idiotypic determinants and MHC determinants using immunoabsorbent columns. Finally, we will use these receptor preparations from cloned T cell lines to determine if one or two different VH gene products are expressed on T cell receptors. From these data we hope to determine the structure of the T cell receptor and its mechanism of binding to various antigenic determinants. Some of our studies will also take advantage of recently prepared monoclonal antibody forming cell lines directed at MHC antigens to both prepare these antigens and to determine their role in T cell antigen recognition and Ir-gene control of T cell responses to antigen.